Agency Response Letter GRAS Notice No. GRN 000425
CFSAN/Office of Food Additive Safety
November 20, 2012
Robert S. McQuate, Ph.D.
GRAS Associates, LLC
20482 Jacklight Lane
Bend, OR 97702-3074
Re: GRAS Notice No. GRN 000425
Dear Dr. McQuate:
The Food and Drug Administration (FDA) is responding to the notice, dated March 6, 2012, that you submitted on behalf of Danone Trading B.V. (Danone) in accordance with the agency’s proposed regulation, proposed 21CFR 170.36 (62 FR 18938; April 17, 1997; Substances Generally Recognized as Safe (GRAS) ); the GRAS proposal). FDA received this notice on March 21, 2012, filed it on March 21, 2012, and designated it as GRN No. 000425.
The subject of the notice is canola oil (low erucic acid rapeseed oil). The notice informs FDA of the view of Danone that canola oil is GRAS, through scientific procedures for use as a source of fat in term infant formulas at levels up to 31% of total fat blend in formula. To meet the requirements for total fat and for levels and ratio of essential fatty acids in infant formula, Danone states that canola oil will be used in combination with other oils in term infant formula.1
As part of its notice, Danone includes the report of a panel of individuals (Danone’s GRAS panel) who evaluated the data and information that are the basis for Danone’s GRAS determination. Danone considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Danone’s GRAS panel discusses chemical and nutritional composition of canola oil, preclinical studies in neonatal pigs fed canola oil with varying levels of erucic acid, clinical studies with infants fed formulas containing canola oil at levels up to 40% of total fats, and uses of canola oil in infant formulas in Europe. Based on this review, Danone’s GRAS panel concluded that canola oil, when produced in compliance with current good manufacturing practices and meeting food grade specifications, is GRAS under the conditions of its intended use.
Danone includes information about the identity and composition of canola oil and discusses differences between canola oil and other vegetable oils commonly used in infant formula. Canola oil contains low levels of erucic acid (≤ 2 %) and slightly higher levels of total phytosterols compared to other vegetable oils. One phytosterol in particular, brassicasterol, is undetectable in other vegetable oils but is present in canola oil. Total phytosterols are less than 1.5% of total fat in canola oil; approximately 10% of phytosterols are brassicasterol. Beta-sitosterol and campesterol, two phytosterols common in other vegetable oils, are the predominant phytosterols in canola oil.
Danone notes that all infant formulas must contain the essential fatty acids linoleic acid (LA; C18:2, n-6) and alpha-linolenic acid (ALA; C18:3, n-3). Danone intends to use canola oil as a source of ALA in term infant formula. Canola oil has a lower LA:ALA ratio than other commonly used oils (e.g., soy). When used in combination with other oils that contain LA, canola oil can be used by infant formula manufacturers to target appropriate levels of LA (8-35% of total fatty acids) and ALA (1.75-4% of total fatty acids) and ensure the fat blend is within the recommended ratio of LA:ALA between 6:1 and 16:1. Danone notes that the upper limit for the ratio of LA:ALA is intended to prevent interference with endogenous formation of n-3 long-chain polyunsaturated fatty acids.
Danone describes production of canola oil in accordance with cGMPs and using food-grade materials. Canola oil is produced from crushing or a combination of crushing and extraction (with hexane) of oilseeds of Brassica rapa or B. napus. When hexane is used to produce canola oil, the solvent is reduced from the oil by distillation, and is fully removed during the deodorization step of oil refining. The maximum residue limit is 1 milligram per kilogram (mg/kg) hexane in canola oil. The canola oil is degummed using water and phosphoric acid and neutralized with diluted food grade alkali. The neutralized oil is then treated with citric acid and bleached using bentonite clay. Each batch of crude canola oil is tested for benzo(a)pyrene (BaP), a heavy polycyclic aromatic hydrocarbon (PAH); if needed, the oil is treated with activated carbon to reduce PAH levels and meet specifications.2 The oil is then filtered and deodorized to remove volatiles, including pesticides and light PAHs. Citric acid is added to the deodorized oil as a metal ion chelator. The fully refined oil is then passed through a final filter prior to packaging.
Danone provides product specifications for canola oil, which is described as a clear pale-yellow oil. In accordance with Food Chemicals Codex (FCC) 8 specifications, Danone includes limits for lead and arsenic (each not more than (NMT) 0.10 mg/kg oil), fatty acids, and various quality parameters (Table 1). The erucic acid specification for Danone’s canola oil is < 1%, which is lower than the FCC 8 specification (NMT 2%). Danone’s specifications also include other contaminants: PAHs NMT 2.0 microgram (μg)/kg for BaP or 2.5 μg/kg for the sum of BaP, chrysene, benz(a)anthracene, and benzo(b)fluoranthene in the refined oil; dioxin-like PCBs NMT 1.5 picograms (pg) WHO-TEQ/g fat; pesticides NMT 10 μg/kg.; dioxins (PCDDs, PCDFs) NMT 1.5 pg WHO-TEQ/grams (g) oil.
|Parameter||GRN 425 Level||FCC 8 Level|
|Oilseed source||B. napus or B. rapa (Fam. Cruciferae)||B. juncea, B. napus, or B. rapa (Fam. Cruciferae)|
|Moisture||NMT 0.05 g/100 g oil (% (w/w))||NMT 0.1%|
|Unsaponifiable matter||NMT 1.5 % (w/w) of oil||Same|
|Free fatty acids||NMT 0.1 % of oil||NMT 0.05%|
|Peroxide value||NMT 0.5 meq O2/kg oil||NMT 10 meq O2/kg oil|
|Iodine value||Between 105 and 125||Between 110 and 126|
|Acid value||NMT 0.5 mg KOH/g oil||NMT 6 mg KOH/g oil|
|Refractive index||1.465 to 1.467 at 40 ºC||Same|
|Fatty acid composition (weight percent of fatty acids)|
|Palmitic acid (16:0)||3.8-5.6 %||NMT 6.0 %|
|Stearic acid (18:0)||1.0-2.5 %||NMT 2.5%|
|Oleic acid (18:1)||56-66 %||NMT 50%|
|Linoleic acid (18:2)||17-23 %||NMT 40.0%|
|Linolenic acid (18:3)||7.0-11.0 %||NMT 14%|
|Arachidic acid (20:0)||NMT 1.0 %||Same|
|Eicosenoic acid (20:1)||NMT 2.0 %||Same|
|Behenic acid (22:0)||NMT 0.5 %||Same|
|Erucic acid||NMT 1%||NMT 2.0%|
Danone also includes microbiological specifications, including limits for aerobic plate count (< 100/g), Enterobacteriacea (< 10/g), yeasts (< 100/g), moulds (< 100/g), Salmonella spp. (negative/25 g), and Chronobacter sakazakii (negative/10 g). Danone notes that aflatoxin, although not a common contaminant in oils, would be removed by bleaching clay. Danone has set a specification of < 0.2 μg/kg for aflatoxin B1.
Danone provides an estimate of canola oil intake for a 6-month old infant (7.9-kg weight) consuming 645 kilocalories per day (kcal/d) of formula containing 5.1 g of fat per 100 kcal (approximately 32.9 g fat per person per day). Using canola oil at 17.5 to 31% of the fat blend in infant formula, the estimated intake of canola oil will be between 5.7 and 10.2 gram per day (g/p/d). Assuming that erucic acid is present at 0.6% of fatty acids and phytosterols phytosterols are present at 900 mg phytosterols per 100 g canola oil (typical levels from batch analyses), the corresponding estimated intakes of erucic acid will be 34-61 milligrams per day (mg/p/d) or 4.3-7.7 milligrams per kilogram of body weight per day (mg/kg bw/d) and of total phytosterols will be 52-91 mg/p/d or 6.5-11.5 mg/kg bw/d. Danone also describes a scenario for infants 3 months of age requiring higher energy intakes of 115 kcal per kilogram per day (kcal/kg/d) (or 540 kcal/d for 4.7 kg infant) that facilitate catch-up growth in infants experiencing growth failure.3 Danone notes that this intake on a body weight basis (115 kcal/kg/d) agrees with published estimates of 95th percentile intakes for males approximately 2-4 months of age. Using canola oil at 17.5 to 31% of the fat blend in infant formula and 5.1 g fat per 100 kcal of formula, the estimated intake of canola oil will be between 4.8 and 8.5 g/p/d for infants consuming 540 kcal/d formula. For the 3-month infants (4.7 kg) described in Danone’s scenario (elevated intake relative to body weight), corresponding erucic acid and phytosterol intakes will be 28.6-50.8 mg/p/d (6.1-10.8 mg/kg bw/d) and 43.2-76.1 mg/d (9.2-16.2 mg/kg/d, respectively).
Danone discusses compositional standards regarding fat and essential fatty acids in infant formula. In addition, the notifier provides a comparison of fatty acid profiles between canola oil and the vegetable oils currently utilized in production of infant formula. The notifier acknowledges the presence of low levels of erucic acid (specification of < 1%) in canola oil. The notifier reviewed and discusses the published scientific literature pertaining to erucic acid safety. This discussion includes the fact that neonatal pigs are better model comparators for humans, because of similar fatty acid metabolism versus rat models. Furthermore, the discussion includes the issue of cardiotoxicity that has been observed in rats and that this is associated with the nutritional and metabolic facts that rats cannot utilize high levels of vegetable oils. Based on these scientific issues, the notifier points to a published study in neonatal piglets receiving blends of rapeseed oil with various erucic acid content levels. Utilizing cardiotoxicity as the safety endpoint, the study authors determined a no observed adverse effect level to be at the 4.9% erucic acid level, which is equivalent to 750 mg/kg bw/d.
Danone also reviewed and discusses published studies in term and pre-term infants fed infant formulas containing canola oil, concluding these studies showed no adverse effects on infant growth. Finally, the notifier provides scientific discussions about vitamin E and platelet levels, concluding vitamin E and platelet levels are of no concern in the context of a balanced infant formula; as well as normal phytosterol levels in canola versus vegetable oils.
Potential Labeling Issues
In describing data and information on clinical studies that Danone relies on to conclude that canola oil is GRAS under the conditions of its intended use, Danone raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act). Under section 403(a) of the FD&C Act, a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FD&C Act lays out the statutory framework for the use of labeling claims that characterize the level of a nutrient in a food or that characterize the relationship of a nutrient to a disease or health-related condition. If products that contain canola oil bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition, Labeling, and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition. The Office of Food Additive Safety neither consulted with ONLDS on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about canola oil on the label or in labeling.
Intended Use in Infant Formula
Under section 412 of the FD&C Act a manufacturer of a new infant formula must make a submission to FDA, providing required assurances about the formula, at least 90 days before the formula is marketed. Danone should be aware that FDA’s response to Danone’s GRAS notice does not alleviate the responsibility of any infant formula manufacturer who intends to market an infant formula that contains canola oil to make the submission required by section 412.
Section 301(ll) of the FD&C Act
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FD&C Act to, among other things, add section 301(ll). Section 301(ll) of the FD&C Act prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FD&C Act, a biological product licensed under section 351 of the Public Health Service Act, or a drug or a biological product for which substantial clinical investigations have been instituted and their existence made public, unless one of the exemptions in section 301(ll)(1)-(4) applies. In its review of Danone’s notice that canola oil is GRAS for the intended use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing canola oil. Accordingly, this response should not be construed to be a statement that foods that contain canola oil, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Danone, as well as other information available to FDA, the agency has no questions at this time regarding Danone’s conclusion that canola oil is GRAS under the intended conditions of use. The agency has not, however, made its own determination regarding the GRAS status of the subject use of canola oil. As always, it is the continuing responsibility of Danone to ensure that food ingredients that the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements.
In accordance with proposed 21 CFR 170.36(f), a copy of the text of this letter responding to GRN 000425, as well as a copy of the information in this notice that conforms to the information in the GRAS exemption claim (proposed 21 CFR 170.36(c)(1)), is available for public review and copying at www.fda.gov/grasnoticeinventory.
Dennis M. Keefe, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
1Exempt and non-exempt term infant formulas are included in the intended use. Danone notes that nutritional requirements of infants are stated in 21 CFR 107.100 and in a 1998 report from the Life Sciences Research Office. FDA has requirements for nutrients in infant formulas, and these are located in section 412(i) of the Federal Food, Drug, and Cosmetic Act and 21 CFR 107.100.
2Danone cites the recent European Commission Regulation (EU) No 835/2011 of 19 August 2011, amending Regulation (EC) No 1881/2006, that sets maximum levels of PAHs (1.0 μg/kg for BaP or the sum of BaP, chrysene, benz(a)anthracene, and benzo(b)fluoranthene) in infant formula. FDA notes that, for most oils and fats intended for direct human consumption or use as an ingredient in foods, the EU set maximum levels at 2.0 μg/kg for BaP and 10.0 μg/kg for the sum of the 4 PAHs.
3Danone cites the Institute of Medicine’s Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (2002/2005) for this discussion of catch-up growth requirements for infants.